Somatic activating BRAF variants cause isolated lymphatic malformations
Kaitlyn Zenner,
Dana M. Jensen,
Victoria Dmyterko,
Giridhar M. Shivaram,
Candace T. Myers,
Cate R. Paschal,
Erin R. Rudzinski,
Minh-Hang M. Pham,
V. Chi Cheng,
Scott C. Manning,
Randall A. Bly,
Sheila Ganti,
Jonathan A. Perkins,
James T. Bennett
Affiliations
Kaitlyn Zenner
Seattle Children’s Hospital, Division of Pediatric Otolaryngology, Department of Otolaryngology/Head and Neck Surgery, University of Washington, Seattle, WA 98195, USA; Vascular Anomalies Program, Seattle Children’s Hospital, Seattle, WA 98105, USA
Dana M. Jensen
Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, WA 98101, USA
Victoria Dmyterko
Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, WA 98101, USA
Giridhar M. Shivaram
Department of Radiology, Division of Interventional Radiology, University of Washington School of Medicine, Seattle, WA, USA
Candace T. Myers
Department of Laboratories, Seattle Children’s Hospital, Seattle, WA 98105, USA
Cate R. Paschal
Department of Laboratories, Seattle Children’s Hospital, Seattle, WA 98105, USA
Erin R. Rudzinski
Department of Laboratories, Seattle Children’s Hospital, Seattle, WA 98105, USA
Minh-Hang M. Pham
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98101, USA
V. Chi Cheng
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98101, USA
Scott C. Manning
Seattle Children’s Hospital, Division of Pediatric Otolaryngology, Department of Otolaryngology/Head and Neck Surgery, University of Washington, Seattle, WA 98195, USA
Randall A. Bly
Seattle Children’s Hospital, Division of Pediatric Otolaryngology, Department of Otolaryngology/Head and Neck Surgery, University of Washington, Seattle, WA 98195, USA; Vascular Anomalies Program, Seattle Children’s Hospital, Seattle, WA 98105, USA
Sheila Ganti
Seattle Children’s Hospital, Division of Pediatric Otolaryngology, Department of Otolaryngology/Head and Neck Surgery, University of Washington, Seattle, WA 98195, USA; Vascular Anomalies Program, Seattle Children’s Hospital, Seattle, WA 98105, USA; Center for Clinical and Translational Research, Seattle Children’s Research Institute, Seattle, WA 98101, USA
Jonathan A. Perkins
Seattle Children’s Hospital, Division of Pediatric Otolaryngology, Department of Otolaryngology/Head and Neck Surgery, University of Washington, Seattle, WA 98195, USA; Vascular Anomalies Program, Seattle Children’s Hospital, Seattle, WA 98105, USA
James T. Bennett
Vascular Anomalies Program, Seattle Children’s Hospital, Seattle, WA 98105, USA; Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, WA 98101, USA; Seattle Children’s Hospital, Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Corresponding author
Summary: Somatic activating variants in PIK3CA, the gene that encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been previously detected in ∼80% of lymphatic malformations (LMs).1,2 We report the presence of somatic activating variants in BRAF in individuals with LMs that do not possess pathogenic PIK3CA variants. The BRAF substitution p.Val600Glu (c.1799T>A), one of the most common driver mutations in cancer, was detected in multiple individuals with LMs. Histology revealed abnormal lymphatic channels with immunopositivity for BRAFV600E in endothelial cells that was otherwise indistinguishable from PIK3CA-positive LM. The finding that BRAF variants contribute to low-flow LMs increases the complexity of prior models associating low-flow vascular malformations (LM and venous malformations) with mutations in the PI3K-AKT-MTOR and high-flow vascular malformations (arteriovenous malformations) with mutations in the RAS-mitogen-activated protein kinase (MAPK) pathway.3 In addition, this work highlights the importance of genetic diagnosis prior to initiating medical therapy as more studies examine therapeutics for individuals with vascular malformations.
